Stroke-like migraine attacks after radiation therapy (SMART) syndrome is not always completely reversible: a case series.

We retrospectively reviewed clinical and imaging findings in 11 patients with stroke-like migraine attacks after radiation therapy (SMART) syndrome to better understand this disorder previously thought to be reversible. Six men and 5 women had complex bouts of neurologic impairment beginning, on average, 20 years after cerebral irradiation. All had characteristic, unilateral gyriform enhancement on MR imaging that developed within 2-7 days and typically resolved in 2-5 weeks. Unlike prior reports, 45% had incomplete neurologic recovery manifesting as dysphasia, cognitive impairment, or hemiparesis. The remaining 55% recovered completely over an average of 2 months. Three of 11 patients developed cortical laminar necrosis. Brain biopsies in 4 of 11 did not demonstrate a specific pathologic substrate. These additional 11 patients contribute to the understanding of variability in stroke-like migraine attacks after radiation therapy syndrome, which often but not uniformly manifests with headaches and seizures, demonstrates a typical evolution of imaging findings, and may result in permanent neurologic and imaging sequelae.

Bilateral autoimmune optic neuritis and vitreitis related to CRMP-5-IgG: intravitreal triamcinolone acetonide therapy of four eyes.

PURPOSE: To report the vision outcome following intravitreal triamcinolone acetonide (IVTA) as adjunctive therapy in four eyes of two patients with paraneoplastic autoimmune optic neuritis and vitreitis related to CRMP (Collapsin-Response-Mediator Protein)-5-IgG. DESIGN: Retrospective case series.MethodsChart review of four eyes. RESULTS: Preoperative visions were: patient 1, 20/50 OD, 20/25 OS; patient 2, counting fingers (CF) at two feet OD, and CF at three feet OS. At last follow-up, the postoperative visions were 20/40, 20/50 and 20/200, 20/60, respectively. All signs of optic disc swelling and vitreitis had abated. CONCLUSIONS: Use of IVTAin paraneoplastic autoimmune optic neuritis and vitreitis related to CRMP-5-IgG was followed by a marked decrease in inflammation and stabilization or improvement of vision. These observations support this form of adjunctive therapy in patients whose intraocular pathology is attributed to paraneoplastic autoimmunity.

SMART: stroke-like migraine attacks after radiation therapy.

We describe two adults with stroke-like migraine attacks after radiation therapy (SMART syndrome), propose revised diagnostic criteria, and review the previously reported patients. 'SMART' is an acronym for a newly recognized syndrome which occurs as a delayed consequence of cerebral irradiation and consists of prolonged, unilateral, migrainous neurological symptoms with transient, dramatic cortical gadolinium enhancement of the affected cerebral hemisphere and is sometimes punctuated by generalized seizures and ipsilateral EEG slowing. Although the neurological symptoms can last for weeks, full recovery occurs. An appropriate evaluation should exclude alternative explanations.

Transgene integration patterns and expression levels in transgenic tissue lines of Picea mariana, P glauca and P abies.

Seventy transgenic tissue lines (translines) of three spruce species ( Picea mariana, P. glauca and P. abies) were characterized with respect to the integration pattern of the gus (beta-glucuronidase) gene, and the level of GUS activity was determined in 81 lines. The majority of the P. mariana translines (18 lines of 22) integrated multicopies of the transgene, whereas mostly single integrations were detected in the other two species. The activity levels of GUS varied widely among the individual translines of P. mariana, and there was a strong indication that the logarithm of GUS activity increased with the number of gus copies ( P=0.0003) in lines with one to five known insertions (uncensored). The average level of GUS activity, in lines that integrated one gene copy, was the highest in white spruce followed by black spruce and Norway spruce (22.7, 16.5 and 6.3 nmol 4-methylumbelliferone min(-1 )mg(-1 )protein, respectively).

Evaluation of microprojectile-mediated DNA delivery and reporter genes for genetic transformation of the Mediterranean cypress (Cupressus sempervirens L.).

Embryonal-suspensor tissue (EST) of Mediterranean cypress (Cupressus sempervirens L.) was tested for microprojectile-DNA delivery (by the PDS-1000/He device) for different subculture periods (9, 15, and 21 days) using the plasmid vectors pRT99GUS [containing the ß-glucuronidase (GUS) and neomycin phosphotransferase (NPT II) genes, and the CaMV 35S promoter], pBI426 (with a GUS::NPT II fusion gene under the control of a duplicated 35S RNA promoter), and pCGUδ0 (containing the GUS gene with the ubiquitin intron, under the control of the sunflower ubiquitin promoter). The relative strengths of the promoters as determined by GUS assays were sunflower ubiquitin>35S-35S-AMVE>35S. The highest expression level was observed when 15-day-subcultured EST was bombarded with the pCGUδ0 gene construct, which also showed high activity of the chloramphenicol acetyltransferase and NPT II genes. Green fluorescent areas were observed on EST when bombarded with the p35S-GFP plasmid, carrying the gene for the green fluorescent protein from the bioluminescent jellyfish Aequorea victoria.

Hypoglycemic effects of peroxovanadium compounds in Sprague-Dawley and diabetic BB rats.

Highly purified peroxovanadium (pV) compounds, each containing an oxo ligand, one or two peroxo anions, and an ancillary ligand in the inner coordination sphere of vanadium, were shown to decrease plasma glucose markedly in both normal Sprague-Dawley and insulin-deprived diabetic BB rats. Maximal decreases in plasma glucose were at 60-100 min after intravenous, intraperitoneal, or subcutaneous administration. Synergism between these compounds and insulin was observed. Whereas parenterally administered orthovanadate or vanadyl sulfate did not induce hypoglycemia before inducing acute mortality, pV compounds effected hypoglycemia at doses much lower than those inducing acute mortality. When administered subcutaneously over a period of 3 days to insulin-deprived diabetic BB rats, pV compounds, but not vanadate, caused a significant decrease in plasma glucose concentrations and prevented the appearance of ketosis in these animals. Thus, pV compounds are the first agents other than insulin that acutely and markedly reduce plasma glucose in hypoinsulinemic diabetic BB rats.

Cyclophosphamide in combination with sargramostim for treatment of recurrent medulloblastoma.

Thirteen patients with recurrent medulloblastoma were treated with cyclophosphamide in association with Sargramostim. Cyclophosphamide was given at doses ranging between 1.0-2.5 g/m2 daily for two doses. Sargramostim was given at a fixed dose of 250 micrograms/m2 subcutaneously twice a day beginning 24 hours after the second cyclophosphamide dose and continuing through the leukocyte nadir until the ANC was more than 1,000 cells/microliters for two consecutive days. A total of 33 courses were given with toxicity consisting of grade 4 neutropenia in all courses and grade 3-4 thrombocytopenia in 10 of 13 patients. There were no deaths related to infection or bleeding. Four patients were taken off study because of prolonged myelosuppression. Three of these patients were at the 2.5 g/m2 level, and of these three, two developed lung toxicity (grades 2 and 4, respectively). One patient developed an allergic reaction following the first injection of Sargramostim and was also taken off study. Of 10 evaluable patients, there were 9 PR and 1 SD. We conclude that cyclophosphamide at a dose of 2.0 g/m2/day x 2 days q 4 weeks in association with Sargramostim demonstrates marked activity with acceptable toxicity in patients with recurrent medulloblastoma.

Dose escalation trial of cyclophosphamide with Sargramostim in the treatment of central nervous system (CNS) neoplasms.

We conducted a dose escalation trial of cyclophosphamide plus Sargramostim in the therapy of patients with newly diagnosed or recurrent central nervous system tumors. Cyclophosphamide was administered at doses ranging between 1.0 and 2.5 g/m2 daily for two doses. Sargramostim was administered at a fixed dose of 250 micrograms/m2 subcutaneously twice a day beginning 24 hours after the second cyclophosphamide dose and continuing through the leukocyte nadir until the absolute neutrophil count (ANC) was > 1,000 cells/microliters for two consecutive days. The MTD for patients who had not received any prior chemotherapy and who had received either no radiotherapy or radiotherapy confined to the cranium was 2.0 g/m2 daily for two doses. The MTD for patients previously treated with chemotherapy or neuraxis radiotherapy was also 2.0 g/m2 daily for two doses. Responses were seen in patients with medulloblastoma (8/9), glioblastoma multiforme (2/13), germinoma (1/1), and pineoblastoma (1/2).

In vivo insulin mimetic effects of pV compounds: role for tissue targeting in determining potency.

Peroxovanadium (pV) compounds activate the insulin receptor kinase in hepatocytes and inhibit the dephosphorylation of insulin receptors in hepatic endosomes with highly correlated potencies (Posner, B. I., R. Faure, J. W. Burgess, A. P. Bevan, D. Lachance, G. Zhang-Sun, J. B. Ng, D. A. Hall, B. S. Lum, and A. Shaver J. Biol. Chem. 269: 4596-4604, 1994). After intravenous administration, K2[VO(O2)2(picolinato)].2H2O [bpV(pic)], VO(O2) (picolinato) (H2O)2 [mpV(pic)], K[VO(O2)2(picolinato)].3H2O [bpV(phen)], and K[VO(O2)2(4,7-dimethyl-1,10-phenanthroline)].1/2H2O [bpV(Me2phen)] produced 50% of their maximal hypoglycemic effect at doses of 0.04, 0.04, 0.32, and 0.65 mumol/100 g body wt, respectively. In contrast, their potencies as inhibitors of dephosphorylation were bpV(pic) = bpV(phen) > mpV(pic) = bpV(Me2phen). bpV(pic) stimulated [14C]glucose incorporation into rat diaphragm glycogen in vivo, and its effect was dose dependent, synergistic with insulin, and evident in other skeletal muscles. In contrast, bpV(phen) displayed no effect on glycogen synthesis in skeletal muscle. mpV(pic) stimulated and bpV(Me2phen) had no effect on glycogen synthesis in the diaphragm. bpV(pic) augmented rat diaphragm insulin receptor kinase 2.2-fold with a time-integrated response 70% that of insulin. In contrast, the effect of bpV(phen) was delayed and much reduced. Thus, the in vivo potencies of pV compounds reflect differing capacities to act on skeletal muscle. The ancillary ligand within the pV complex may target one tissue in preference to another.

Cyclophosphamide, doxorubicin, vincristine, and prednisone for primary central nervous system lymphoma: short-duration response and multifocal intracerebral recurrence preceding radiotherapy.

The activity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the treatment of primary central nervous system lymphoma (PCNSL) prior to radiotherapy was studied in six patients. Primary lesions were reduced by 80% or more on contrast-enhancing cross-sectional area in four patients and to a lesser extent in two others after two cycles of chemotherapy. The primary lesion sites demonstrated no contrast enhancement in the three patients who completed four cycles of therapy. However, concurrent with response at the primary disease sites, multiple lesions occurred at distant, noncontiguous CNS parenchymal sites in five patients after two to four cycles of chemotherapy. Median survival was 8.5 months for the six enrolled patients and 16.5 months for the four patients completing craniospinal radiotherapy. PCNSL is highly responsive to standard systemic non-Hodgkin's lymphoma chemotherapy regimens, but the pattern and rapidity of relapse suggest mechanisms of failure including inherent or rapidly evolving antineoplastic drug resistance and perhaps limited drug delivery to occult sites of disease in the brain.

Peroxovanadium compounds. A new class of potent phosphotyrosine phosphatase inhibitors which are insulin mimetics.

Twelve peroxovanadium (pV) compounds, each containing an oxo ligand, one or two peroxo anions, and an ancillary ligand in the inner coordination sphere of V, were synthesized, crystallized, and characterized by 51V NMR as > 95% pure. These compounds activated the insulin receptor kinase (IRK) of cultured hepatoma cells, stimulated lipogenesis in adipocytes, and inhibited the in situ dephosphorylation of autophosphorylated IRs and epidermal growth factor receptors of rat liver endosomes. The phosphotyrosine phosphatase inhibitory and IRK activating potencies of these compounds were linearly correlated (r = 0.74; p < 0.003), decayed in parallel in solution, and varied considerably with the ancillary ligands within these compounds. In vivo administration activated rat liver IRK in parallel with its tyrosine phosphorylation. Co-administration of insulin plus pV was markedly synergistic in both respects. pV administration significantly decreased circulating insulin and plasma glucose concentrations; the latter to levels seen after a dose of insulin yielding > or = 50% occupancy of IRs in vivo. Two compounds (mpV(pic) and mpV(2,6-pdc)) displayed relative specificity as phosphotyrosine phosphatase inhibitors by inhibiting IR dephosphorylation to a significantly greater degree than epidermal growth factor receptor dephosphorylation. Thus, pV compounds are the most potent phosphotyrosine phosphatase inhibitors described to date. Their capacity to activate IRK appears to derive from their phosphotyrosine phosphatase inhibitory activity. Their hypoglycemic action is due to a direct tissue effect.

Microprojectile-DNA delivery in conifer species: factors affecting assessment of transient gene expression using the ß-glucuronidase reporter gene.

The Biolistic(®) microprojectile DNA-delivery method was used to test the usefulness in conifers of eight gene constructs based on the 35S promoter, the AMV translational enhancer, and gene fusion between the P-glucuronidase and the neomycin phosphotransferase II genes. The evaluation was done with embryogenic cells of Picea glauca, where the relative strengths of the promoters were 35S-35S-AMVE>35S-AMVE>35S-35S>35S as evaluated by transient gene expression. The fusion gene of GUS and NPT II gave lower levels of transient gene expression than the unfused GUS gene as detected by X-GLU histochemical assays. Experiments comparing the EM promoter of wheat and the 35S-35S-AMVE promoter (with and without fusion between GUS and NPT II) were done in Picea rubens, P. mariana, P. glauca, and Larix x eurolepis. The unfused gene with the 35S-35S-AMVE promoter gave higher levels of transient gene expression than the fused GUS-NPT II gene. The fluorescent MUG assay was more sensitive than the histochemical X-GLU assay to detect the activity of the ß-glucuronidase gene.

Acute peripheral arterial occlusion: electrophysiologic study of 32 cases.

Thirty patients with 32 acute peripheral arterial occlusions underwent nerve conduction and electromyographic studies at a mean of 12.4 months after the vascular occlusion. Compound action potentials showed greater reduction than conduction velocity (26% to 75% vs 8% to 13% lower than normal). All changes were more prominent in the legs than arms, including fibrillation potentials (64% vs 28%). Short motor unit potentials were seen in 13% of patients; this group also had signs of severe nerve damage. The extent of abnormality varied with location of occlusion. Signs of nerve damage were significantly decreased in patients who had early revascularization. The electrophysiologic findings suggested axonal destruction rather than demyelination.

Neither ventricles nor afterload relief influence the raised plasma atrial natriuretic factor induced by volume expansion in the spontaneously hypertensive rat.

STUDY OBJECTIVE: The aims were (1) to study the influence of afterload relief on the rise in atrial natriuretic factor (ANF) which occurs during acute volume expansion in the spontaneously hypertensive rat (SHR); (2) to assess the contribution of the atria and the ventricles to ANF release under these circumstances. DESIGN: In the first series of experiments, SHR were treated with captopril (150 mg.kg-1.d-1) orally for 10 d. Untreated SHR and Wistar-Kyoto (WKY) rats served as controls. Volume expansion, equivalent to 10% of the total blood volume, was performed three times with human plasma protein fraction at 15 min intervals on conscious animals. Some haemodynamic variables and plasma ANF were measured. Tissue ANF measurements were conducted on another series of treated and control SHR not submitted to volume expansion. In another series of experiments, conscious SHR and WKY rats were submitted to repetitive 30% volume expansion (three times at 15 min intervals). Non-expanded animals served as controls. At the end of the experiments, tissue ANF measurements were performed. EXPERIMENTAL MATERIAL: All experiments were conducted on 15 week old SHR and WKY rats. MEASUREMENTS AND MAIN RESULTS: Captopril treatment reduced systolic blood pressure and cardiac hypertrophy in SHR. During volume expansion, changes in left ventricular end diastolic pressure were greater in control SHR than in treated SHR or WKY rats. Central venous pressure was affected similarly by volume expansion in both SHR groups. Plasma ANF rises induced by volume expansion were equal in all groups. Captopril treatment had no effect on right or left auricular ANF content prior to volume expansion. Repetitive 30% expansion reduced both right and left auricular ANF concentrations to the same extent (approximately 300-1500 ng.mg-1 protein) in SHR and WKY groups. Ventricular ANF was not affected by volume expansion in SHR, whereas volume expanded WKY rats had higher right and left ventricular ANF concentrations than their non-expanded controls. CONCLUSIONS: (1) The increase in plasma ANF during volume expansion is not impaired in SHR with newly established hypertension; (2) captopril treatment decreases afterload and the changes in left ventricular end diastolic pressure during volume expansion in SHR, without affecting plasma ANF increases; (3) both the auricles, but not the ventricles, contribute to enhanced ANF secretion caused by acute volume expansion in SHR and WKY rats.

Synergism of atrial pressure and adrenergic stimulation for ANF release in the rat.

The effect of adrenergic stimulation on atrial natriuretic factor (ANF) release was studied in conscious rats. 60 min i.v. infusion of 15 micrograms/kg/min phenylephrine produced an elevation in mean arterial pressure of about 50 mmHg that was associated with an immediate, transitory increase in both central venous (CVP) and left ventricular end-diastolic (LVEDP) pressures. Heart rate was not changed. The elevation in CVP, but not LVEDP, persisted until 5 min, together with a 50-fold increase in plasma C-terminal ANF concentrations (from 19 +/- 5 to 1010 +/- 339 fmol/ml); at 30 min, in the absence of any increases in CVP or LVEDP, plasma ANF was still elevated by 5-fold (114 +/- 35 fmol/ml). It is suggested that adrenergic stimulation 'per se' can induce ANF release, independently of atrial pressure. Furthermore, combined adrenergic stimulation and increased atrial wall tension could result in a potentiation of the ANF secretory response 'in vivo', in the case where both stimuli are present concomitantly.

Atrial natriuretic factor release during acute infusion of isoproterenol in the conscious rat.

The effect of beta-adrenergic stimulation on atrial natriuretic factor (ANF) release was studied in conscious rats. 20-min infusion of 85 or 850 ng kg-1 min-1 isoproterenol (ISO) resulted in positive inotropic and chronotropic responses and no elevation of atrial pressures. A slight increase in plasma ANF, together with a drop in blood pressure, were observed only in the group infused with the higher dose. During the infusion of 850 ng kg-1 min-1 ISO, there was no relationship between plasma ANF and any of the haemodynamic parameters, with the exception of mean arterial pressure (r = 0.72, P less than 0.05, n = 9). Larger doses (greater than 3 micrograms kg-1 min-1) were toxic. We conclude that beta-adrenergic stimulation is not an important stimulus for ANF release when diastolic resting tension is low.

Primary leptomeningeal lymphoma: report of 9 cases, diagnosis with immunocytochemical analysis, and review of the literature.

We describe 9 patients who presented with a neoplastic meningitis of lymphomatous origin. No evidence of parenchymal central nervous system or systemic tumor was identified either at the time of presentation or throughout the course of their disease. We have chosen to call this entity "primary leptomeningeal lymphoma" (PLML). This unusual form of neurologic lymphoma must be differentiated from the more common clinical situations of primary parenchymal lymphoma with meningeal involvement and systemic lymphoma complicated by lymphomatous meningitis.

Atrial natriuretic factor release during volume expansion in the spontaneously hypertensive rat--effect of long-term hydralazine treatment.

We tested the ability of spontaneously hypertensive rats (SHR) to release atrial natriuretic factor (ANF) during acute volume loading and its relationship to right and left atrial pressures. The effect of decreasing cardiac afterload by hypotensive treatment was also investigated. Fourteen to 15-week-old SHR and Wistar-Kyoto (WKY) rats were treated with hydralazine (12 mg/kg.day p.o.) for a period of 4 weeks. Untreated rats served as controls. The systolic blood pressure (BP) of SHR decreased to normotensive levels and cardiac hypertrophy was also reduced. Isotonic, iso-oncotic volume expansion (VE) was performed 3 times as 10% increments and at 15-min intervals. Despite greater changes in left-ventricular end-diastolic pressures (LVEDP) and to a lesser extent in central venous pressure (CVP) in SHR controls, the increases in plasma ANF (N-terminal concentrations) induced by VE were of a similar magnitude in both SHR and WKY control rats. The LVEDP and ANF C-terminal elevations were of a lower magnitude in treated SHR. Auricular ANF concentrations, measured at the end of VE, were lower in the left and higher in the right atrium in SHR versus WKY. It is concluded that despite a lower distensibility of their left atrium, ANF release is not impaired in SHR upon a VE. This adequate ANF release is obtained through higher increases in atrial pressures.

Atrial natriuretic factor and volume expansion-induced natriuresis in the spontaneously hypertensive rat.

The implication of atrial natriuretic factor (ANF) during acute volume expansion in the spontaneously hypertensive rat (SHR) was evaluated. The effect of short-term afterload relief was also investigated. Fourteen- to 15-week-old SHR and Wistar-Kyoto (WKY) rats were treated with hydralazine for 5 days. The systolic blood pressure (BP) of SHR decreased to normotensive levels but cardiac hypertrophy was not reduced. Isotonic, iso-oncotic volume expansion (equivalent to 10% of total blood volume) was performed 3 times at 15-min intervals on conscious animals. The effect of volume expansion on central venous pressure was identical among the groups. Changes in left ventricular end-diastolic pressure (LVEDP) induced by volume expansion were greater in SHR than in WKY rats and were not affected by treatment. The increases in plasma N-terminal ANF (ANF-(1-98)) concentrations were larger in both treated and untreated SHR verses WKY rats. Despite enhanced ANF release in SHR, the overall magnitude of the diuretic and natriuretic responses to volume expansion was similar in all groups. The natriuretic response was strongly correlated with plasma ANF in WKY rats, this relationship was weak in control SHR, and restored by treatment. It is suggested that ANF release is not impaired in SHR at a 10% volume load; however, there seems to be a lower renal responsiveness to ANF in SHR.